[MIM 613 068]

(Neurodegenerative syndrome due to cerebral deficit in the transport of folates, cerebral folates transport deficit)

Recently identified disease caused by a disorder of the intracerebral transport of folates.

Food folates are transformed in the liver 5-methyltetrahydrofolates. Their intracellular transport involves carrier proteins (PCFT and RFC)  and specific receptors (FR-α and FR-β). These receptors are present in the choroid plexus and are the main transporter of 5-methyltetrahydrofolates across the blood-brain barrier: FR-β is expressed during fetal life and its activity declines between 4 and 6 months after birth.  5-methyltetrahydrofolates are cofactors in the synthesis of many neurotransmitters and play an important role in myelination. 

In case of intracerebral folate deficiency, blood folate levels are normal but 5-methyltetrahydrofolates level in the CSF is low.

Two causes have been identified:

-         the presence of autoantibodies directed  against the membrane receptors involved in the intracerebral transport of folate. Normal development until 4-6 months then onset of agitation and sleep disorders. Later, hypotonia with spasticity of the lower limbs, delay or lack of speech. Epilepsy in 1/3 of cases, autistic behavior in 1/3 of cases, dyskinesia in 1/3 of cases.

-        a congenital deficiency in FR-α receptors [MIM 613 068] due to a mutation (sporadic or by autosomal recessive transmission) in the  FOLR1 gene  (folate Receptor 1)(11q13.4). First symptoms present after 2 years of age, when FR-β no longer compensates for the lack of FR-α activity: psychomotor regression and ataxia, which progresses to treatment-resistant epileptic encephalopathy, leukodystrophy with hypomyelination and neuromotor impairment.

Treatment: oral high-dose of folates. The results are variable and depend on the precocity of the treatment. IV administration of folates is sometimes necessary.

Anesthetic implications: 

avoid using N2O ? Epilepsy. Mental retardation.

References : 

-         Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S et al. 
Folate receptor alpha defectcauses cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. 
Am J Hum Genetics 2009; 85: 354-63.

-          Ramaekers VT, Rothenberg SP, Sequera JM, Opladen T et al. 
Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. 
N Engl J Med 2005; 352: 1985-91. 

-        Delmelle F, Thony B, Clapuyt P, Blau N, Nassogne MC.
Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation.
Eur J Paediatr Neurol 2016; 20 :709–13.

-        Jaafar F, Obeid M.
Successful treatment of cerebral folate transporter deficiency with intravenous folinic acid.
Pediatr Neurol 2022 ; 135 : 22-4.

-        Potic A, Perrier S, Radovic T, Gavrilovic S, Jelena Ostojic J et al.
Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature.
Orphanet Journal of Rare Diseases 2023; 18:187 doi.org/10.1186/s13023-023-02802-6

Updated: July 2023